Signal transduction pathways through TRK-A and TRK-B receptors in human neuroblastoma cells

Little is known about the signal transduction pathways of TRK family receptors in neuroblastoma (NB) cells. In this study, an NE cell line, designated MP-N-TS, was established from an adrenal tumor taken from a 2-year-old boy. This cell line expressed both TRK-A and TRK-B receptors, which is rare in a single NE cell line. Therefore, the MP-N-TS cell line was used to determine whether the signal transduction through these constitutive receptors is functional. Three neurotrophins, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-4/5 (NT-4/5), induced tyrosine phosphorylation of panTRK, and BDNF and NT-4/5 induced tyrosine phosphorylation of TRK-B, Tyrosine phosphorylation of panTRK and/or TRK-B by the neurotrophins was inhibited in the presence of a tyrosine kinase inhibitor K252a. Tyrosine phosphorylation of Src homologous and collagen (Shc), extracellular signal-regulated kinase (ERK)-1 and ERK-2, and phospholipase C-yl (PLC-yl) was increased by the three neurotrophins and the increase was inhibited in the presence of K252a, Activation of Ras, detected as the GTP-bound form of Res, was induced by the three neurotrophins, The neurotrophins did not modulate the expressions of TRK-A or TRK-B mRNA, but they did induce the expression of c-fos mRNA. Exogenous NGF induced weak neurite outgrowth, whereas exogenous BDNF and NT-4/5 induced distinct neurite outgrowth. Exogenous BDNF and NT-4/5 increased the number of viable tells, while NGF did not. Our results demonstrate that the signal transduction pathways through TRK-A and TRK-B in MP-N-TS cells are functional and similar, and the main downstream signaling pathways from the three neurotrophins are mitogen-activated protein kinase (MAPK) cascades through Shc, activated Ras, ERK-1 and ERK-2, and the transduction pathway through PLC-gammal. Further, BDNF and NT-4/5 increased cell viability, The MP-N-TS cell line should be useful for clarifying the TRK-A and TRK-B signaling pathways responsible for the different prognoses in patients with NB.